Despite advances in our knowledge of Alzheimer's disease (AD) course, our understanding of the pathogenesis of this devastating illness is lagging behind. This application, in response to RFA-AG-15-010, aims to identify the contribution of vascular dysfunction and its associated molecular mechanisms related to the endothelium and angiotensin pathways in AD. We propose to assess systemic and cerebral vascular functions and identify their molecular regulators in prodromal AD and use experimental models to define the precise contribution of these pathways and potential therapeutic interventions. We leverage existing cohorts (Emory Cardiovascular Biobank and Predictive Health Studies); excellent infrastructure for molecular and translational vascular phenotyping; ongoing NIH funded projects (Emory ADRC) at our institution; and a strong interdisciplinary team with expertise in cardiology, vascular biology, cognitive aging, neurosciences, neuroimaging, metabolomics and bioinformatics. To achieve this goal of studying the role of vascular function in AD, we will study 100 individuals with prodromal AD (MCI with AD-signature cerebrospinal fluid (CSF) profile, MCI-AD) and 100 matched cognitively normal individuals for 2 years and use a novel AD rat model (TgF344) that exhibits changes in both amyloid and tau also followed for 2 years. Our Aims are to investigate the role of vascular function and regenerative capacity in MCI-AD (AIM1); Identify CSF and plasma markers in vascular other metabolic pathways using explorative unbiased metabolomic profiling in MCI-AD (AIM2); and use a rat AD animal model to establish the chronological order between vascular dysfunction and AD trajectory and study the impact of modifying vascular dysfunction via angiotensin II blockade on AD trajectory (AIM3). Our preliminary work suggests that (i) systemic and cerebral vascular dysfunction contribute to cognitive impairments, and that (ii) molecular/cellular modulators of vascular function (oxidative stress (OS), renin angiotensin aldosterone system, endothelial activity and vascular regeneration) are related to cognitive function and neuropathological indicators of AD. We intend to build on this prior work and will leverage ongoing studies to ensure recruitment of the proposed sample (n=200). We incorporate a set of parallel measures in the human and rat studies enhancing 2-way translational capabilities: object location cognitive paradigm, A?/tau levels, and comparable measures of vascular. To uncover underlying known and unknown molecular regulators, we have a cutting edge metabolomic facility and use novel metabolomic analysis of CSF and plasma of our participants. We validate the role of significant metabolite in AD in (i) our AD rats using gene expression and (ii) in an independent CSF sample (N=800). Our infrastructure of a strong vascular phenotyping program and a highly accomplished interdisciplinary team put us in a unique place to achieve the goals of this RFA: identify novel vascular biomarkers and provide new vascular-targeted therapies in early AD.